TY - JOUR
T1 - The Microbiota Promotes Arterial Thrombosis in Low-Density Lipoprotein Receptor-Deficient Mice
AU - Kiouptsi, Klytaimnistra
AU - Jaeckel, Sven
AU - Pontarollo, Giulia
AU - Grill, Alexandra
AU - Kuijpers, Marijke J. E.
AU - Wilms, Eivor
AU - Weber, Christian
AU - Sommer, Felix
AU - Nagy, Magdolna
AU - Neideck, Carlos
AU - Jansen, Yvonne
AU - Ascher, Stefanie
AU - Formes, Henning
AU - Karwot, Cornelia
AU - Bayer, Franziska
AU - Kollar, Bettina
AU - Subramaniam, Saravanan
AU - Molitor, Michael
AU - Wenzel, Philip
AU - Rosenstiel, Philip
AU - Todorov, Hristo
AU - Gerber, Susanne
AU - Walter, Ulrich
AU - Jurk, Kerstin
AU - Heemskerk, Johan W. M.
AU - van der Vorst, Emiel P. C.
AU - Doering, Yvonne
AU - Reinhardt, Christoph
PY - 2019
Y1 - 2019
N2 - Atherosclerotic plaque development depends on chronic inflammation of the arterial wall. A dysbiotic gut microbiota can cause low-grade inflammation, and microbiota composition was linked to cardiovascular disease risk. However, the role of this environmental factor in atherothrombosis remains undefined. To analyze the impact of gut microbiota on atherothrombosis, we rederived low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice as germfree (GF) and kept these mice for 16 weeks on an atherogenic high-fat Western diet (HFD) under GF isolator conditions and under conventionally raised specific-pathogen-free conditions (CONVR). In spite of reduced diversity of the cecal gut microbiome, caused by atherogenic HFD, GF Ldlr(-/-) mice and CONV-R Ldlr(-/-) mice exhibited atherosclerotic lesions of comparable sizes in the common carotid artery. In contrast to HFD-fed mice, showing no difference in total cholesterol levels, CONV-R Ldl(-/-) mice fed control diet (CD) had significantly reduced total plasma cholesterol, very-low-density lipoprotein (VLDL), and LDL levels compared with GF Ldlr(-/-) mice. Myeloid cell counts in blood as well as leukocyte adhesion to the vessel wall at the common carotid artery of GF Ldlr(-/-) mice on HFD were diminished compared to CONV-R Ldlr(-/-) controls. Plasma cytokine profiling revealed reduced levels of the proinflammatory chemokines CCL7 and CXCL1 in GF Ldlr(-/-) mice, whereas the T-cell-related interleukin 9 (IL-9) and IL-27 were elevated. In the atherothrombosis model of ultrasound-induced rupture of the common carotid artery plaque, thrombus area was significantly reduced in GF Ldlr(-/-) mice relative to CONV-R Ldlr(-/-) mice. Ex vivo, this atherothrombotic phenotype was explained by decreased adhesion-dependent platelet activation and thrombus growth of HFD-fed GF Ldlr(-/-) mice on type III collagen.IMPORTANCE Our results demonstrate a functional role for the commensal microbiota in atherothrombosis. In a ferric chloride injury model of the carotid artery, GF C57BL/6J mice had increased occlusion times compared to colonized controls. Interestingly, in late atherosclerosis, HFD-fed GF Ldlr(-/-) mice had reduced plaque rupture-induced thrombus growth in the carotid artery and diminished ex vivo thrombus formation under arterial flow conditions.
AB - Atherosclerotic plaque development depends on chronic inflammation of the arterial wall. A dysbiotic gut microbiota can cause low-grade inflammation, and microbiota composition was linked to cardiovascular disease risk. However, the role of this environmental factor in atherothrombosis remains undefined. To analyze the impact of gut microbiota on atherothrombosis, we rederived low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice as germfree (GF) and kept these mice for 16 weeks on an atherogenic high-fat Western diet (HFD) under GF isolator conditions and under conventionally raised specific-pathogen-free conditions (CONVR). In spite of reduced diversity of the cecal gut microbiome, caused by atherogenic HFD, GF Ldlr(-/-) mice and CONV-R Ldlr(-/-) mice exhibited atherosclerotic lesions of comparable sizes in the common carotid artery. In contrast to HFD-fed mice, showing no difference in total cholesterol levels, CONV-R Ldl(-/-) mice fed control diet (CD) had significantly reduced total plasma cholesterol, very-low-density lipoprotein (VLDL), and LDL levels compared with GF Ldlr(-/-) mice. Myeloid cell counts in blood as well as leukocyte adhesion to the vessel wall at the common carotid artery of GF Ldlr(-/-) mice on HFD were diminished compared to CONV-R Ldlr(-/-) controls. Plasma cytokine profiling revealed reduced levels of the proinflammatory chemokines CCL7 and CXCL1 in GF Ldlr(-/-) mice, whereas the T-cell-related interleukin 9 (IL-9) and IL-27 were elevated. In the atherothrombosis model of ultrasound-induced rupture of the common carotid artery plaque, thrombus area was significantly reduced in GF Ldlr(-/-) mice relative to CONV-R Ldlr(-/-) mice. Ex vivo, this atherothrombotic phenotype was explained by decreased adhesion-dependent platelet activation and thrombus growth of HFD-fed GF Ldlr(-/-) mice on type III collagen.IMPORTANCE Our results demonstrate a functional role for the commensal microbiota in atherothrombosis. In a ferric chloride injury model of the carotid artery, GF C57BL/6J mice had increased occlusion times compared to colonized controls. Interestingly, in late atherosclerosis, HFD-fed GF Ldlr(-/-) mice had reduced plaque rupture-induced thrombus growth in the carotid artery and diminished ex vivo thrombus formation under arterial flow conditions.
KW - gut microbiota
KW - germfree
KW - low-density lipoprotein receptor
KW - arterial thrombosis
KW - atherothrombosis
KW - carotid artery
KW - atherosclerosis
KW - microbiota
KW - platelets
KW - vascular inflammation
KW - GUT MICROBIOTA
KW - PLATELET HYPERREACTIVITY
KW - CHLAMYDIA-PNEUMONIAE
KW - GLYCOPROTEIN-VI
KW - ATHEROSCLEROSIS
KW - INFLAMMATION
KW - RECRUITMENT
KW - METABOLISM
KW - ACTIVATION
KW - COAGULATION
U2 - 10.1128/mBio.02298-19
DO - 10.1128/mBio.02298-19
M3 - Article
C2 - 31641089
VL - 10
JO - Mbio
JF - Mbio
SN - 2150-7511
IS - 5
M1 - e02298-19
ER -